We propose to establish a NIDA Center of Excellence for Computational Drug Abuse Research (CDAR) between the University of Pittsburgh (Pitt) and (CMU), with the goal of advancing and ensuring the productive and broad usage of state-of-the-art computational technologies that will facilitate and enhance drug abuse (DA) research, both in the local (Pittsburgh) area and nationwide. To this end, we will develop/integrate tools for DA-domain-specific chemical-to-protein-to-genomics mapping using cheminformatics, computational biology and computational genomics methods by centralizing computational chemical genomics (or chemogenomics) resources while also making them available on a cloud server. The Center will foster collaboration and advance knowledge-based translational research and increase the effectiveness of ongoing funded research project (FRPs) via the following Research Support Cores: (1) The Computational Chemogenomics Core for DA (CC4DA) will help address polydrug addiction/polypharmacology by developing new chemogenomics tools and by compiling the data collected/generated, along with those from other Cores, into a DA knowledge-based chemogenomics (DA-KB) repository that will be made accessible to the DA community. (2) The Computational Biology Core (CB4DA) will focus on developing a resource for structure-based investigation of the interactions among substances of DA and their target proteins, in addition to assessing the drugability of receptors and transporters involved in DA and addiction. These activities will be complemented by quantitative systems pharmacology methods to enable a systems-level approach to DA research. (3) The Computational Genomics Core (CG4DA) will carry out genome-wide discovery of new DA targets, markers, and epigenetic influences using developed machine learning models and algorithms. (4) The Administrative Core will coordinate Center activities, provide management to oversee the CDAR activities in consultation with the Scientific Steering Committee (SSC) and an External Advisory Board (EAB), ensure the effective dissemination of software/data among the Cores and the FRPs, and establish mentoring mechanisms to train junior researchers. Overall, the Center will strive to achieve the long-term goal of translating advances in computational chemistry, biology and genomics toward the development of novel personalized DA therapeutics.